The present invention relates to drugs, particularly to novel isoquinoline derivatives or salts having a If current inhibitory effect without serious side effects such as convulsion and also to drugs, particularly cardiac rate lowering agents containing these compounds as the active ingredient.
With regard to drugs having a cardiac rate lowering effect, there have been known neurotransmitter receptors and drugs acting on ion channels, and representative examples of the former are adenosine receptor agonists, M2 muscarinic receptor agonists and xcex2-adrenergic receptor antagonists, while those of the latter are calcium channel blockers. Such drugs which lower the cardiac rate have been confirmed to be useful as preventive and therapeutic agents for various clinical symptoms caused by imbalance between supply and demand of oxygen in cardiac muscles, for example, ischemic heart diseases such as angina and cardiac infarction and circulatory diseases such as arrhythmia and cardiac insufficiency. However, these drugs have not only a cardiac rate lowering effect but also an excessive suppressing effect to atrioventricular conduction and systolic function or a hypotensive effect. In some cases, they may express an action which results in a complete cardiac arrest and, therefore, their use especially to patients whose cardiac function lowers has been worried about.
On the other hand, it has been known that electrical excitation spontaneously takes place in sinoatrial node having a physiological cardiac pacemaker action, atrioventricular node constituting conduction system and cells such as His bundle and Purkinje fiber. In the cells having a cardiac pacemaker action, there has been confirmed the presence of an ionic current having no selectivity in permeation to cations such as sodium ion and potassium ion, being activated by hyperpolarization of membrane potential and being activated by stimulation with a xcex2 receptor, which is named a If current (Difrancesco, D., et al., J. Physiol., 377:61-88, 1986; Irisawa, H., et al., Physiol. Rev., 73:197-227, 1993; and Difracesco, D., Annu. Rev. Physiol.,55:455-472, 1993). It is believed that, in heart, the If current is a current which contributes in the formation of diastolic depolarization of the cells having a pacemaker effect and carries out cardiac rate adjustment.
Accordingly, there has been expected an effect of lowering the cardiac rate by inhibiting the If current regulating the inclination of the diastolic depolarization. In fact, pharmaceuticals of a new type which express the cardiac rate lowering effect by inhibiting the If current have been reported recently. Such If current inhibitors are able to selectively lower the cardiac rate without excessive suppression of atrioventricular conduction and systolic function and also able to reduce the oxygen consumption of cardiac muscle. Accordingly, the current If inhibitors are discriminated from the activity of the conventional various receptor agonists and calcium channel blockers due to the absence of an excessive suppressive effect to atrioventricular conduction and systolic function or of a cardiac arrest effect. Therefore, the If current inhibitors are expected to be able to be preventive and therapeutic agents for ischemic diseases (such as angina and cardiac infarction) and circulatory diseases (such as arrhythmia and cardiac insufficiency) with little side effects. They are also useful to suppress an excessively increased cardiac rate so as to control the cardiac rate to a predetermined state in operations under anesthesia, etc.
It has been further reported that an ionic current having a similar property to the If current (having no selectivity in permeation to cations, being activated by hyperpolarization and being activated by stimulation with a xcex2 receptor) is present not only in the cells having a pacemaker effect but also in inherent cardiac muscle cells usually having no pacemaker effect such as atrial muscle and ventricular muscle cells (Hangang Yu, Circ. Res., 72:232-236, 1993). In some types of symptoms of cardiac insufficiency, hypertension or the like, electrical excitation is spontaneously resulted even in the intrinsic cardiac muscle cells and, when effect potential is recorded from those cells, there is observed diastolic depolarization where membrane potential is gradually depolarized during the electrical diastole after the effect potential is repolarized. In such symptom, an increase in the If current is confirmed, and it is presumed that the If current contributes in the formation of this diastolic depolarization causing acceleration of ectopic automatism or triggered activity (Elizabetta, C., et al., Circulation, 94:1674-1681, 1996; and Elizabetta, C., et al., Circulation, 95:568-571, 1997). Accordingly, it has been believed that the If current inhibitors are useful for the suppression of the acceleration of ectopic automatism or triggered activity in those symptoms.
It has been known that the effect of zatebradine which is known as a compound having a cardiac rate lowering effect is based on the If current inhibitory effect. However, it has been reported that zatebradine expresses a cardiac rate lowering effect and a visual disorder (William H. Frishman, J. Am. Coll. Cardiol., 26:305-312, 1995; and Stephen P. Glasser, et al., The American Journal of Cardiology, 79:1401-1405, 1997). It has been known that another current (Ih current) having a similar property to the If current is present in visual cells (Shaul Hestrin, J. Physiol., 390:319-333, 1987). But, since zatebradine inhibits the Ih current together with the If current, such visual disorder is presumed to be expressed thereby. In the study of the If current inhibitors, separation from the Ih current inhibitory effect is one of the propositions.
With regard to the compound having an anti-tachycardiac effect or a vasodilating effect, xcex2-amino acid amide derivatives represented by the following general formula have been reported (Japanese Patent Laid-Open No. 138172/1990). However, there is no description for the If current inhibitory effect. 
(As to the symbols in the formula, refer to the above-mentioned patent.)
In addition, the present inventors have reported that 2-(3-piperidyl)-1,2,3,4-tetrahydroisoquinoline derivatives represented by the following general formula as the compounds having a cardiac rate lowering effect (WO 98/13364). 
(As to the symbols in the formula, refer to the above-mentioned patent.)
The present inventors have carried out intensive investigations for the drugs which inhibit the If current. As a result, it has been found that isoquinoline derivatives represented by the following general formula (I) inhibit the If current and have a cardiac rate lowering effect in the heart and confirmed that the derivatives are not accompanied by serious side effects such as convulsion, leading to completion of the present invention.
Specifically, the present invention relates to an isoquinoline derivative represented by the following general formula (I) or a salt thereof and also to drugs, particularly a If current inhibitor or, more particularly, a cardiac rate lowering agent, a therapeutic agent for cardiac insufficiency and a therapeutic agent for arrhythmia, containing the derivative or its salt as an effective ingredient. 
(The symbols in the above formula have the following meanings:
A: lower alkylene;
B: xe2x80x94C(xe2x95x90O)xe2x80x94NR5xe2x80x94 or xe2x80x94NR5xe2x80x94C(xe2x95x90O)xe2x80x94;
R1 and R2: hydrogen atom, lower alkyl or xe2x80x94O-lower alkyl, which may be the same or different;
R3, R4 and R5: hydrogen atom or lower alkyl, which may be the same or different;
ring D: optionally substituted hydrocarbon ring or optionally substituted hetero ring;
m: 1, 2 or 3;
n: 0 or 1; and
q: 1 or 2.)
The compounds of the present invention have a characteristic feature that an amide moiety is always available in the structural formula and have an excellent profile that they exhibit a strong If current inhibitory effect without side effects such as convulsion.
As hereunder, the compound (I) of the present invention will be illustrated in detail.
In the definition for the general formula of the present invention, the term xe2x80x9clowerxe2x80x9d means a linear or branched carbon chain having 1 to 6 carbon atoms unless otherwise mentioned.
As to the xe2x80x9clower alkylxe2x80x9d, preferred one is a lower alkyl having 1 to 4 carbon atoms, and more preferably, methyl, ethyl, propyl or isopropyl. As to the xe2x80x9clower alkylenexe2x80x9d, the preferred one is methylene, ethylene, propylene or methylmethylene.
In the formula, 
is preferably 
Among them, six-membered ones are particularly preferred.
The xe2x80x9chydrocarbon ringxe2x80x9d is a saturated or unsaturated, monocyclic or fused hydrocarbon ring, and xe2x80x9carylxe2x80x9d or xe2x80x9ccycloalkylxe2x80x9d is exemplified, with the xe2x80x9carylxe2x80x9d being particularly preferred.
The xe2x80x9carylxe2x80x9d is preferably an aryl having 6 to 14 carbon atoms, including a dihydro group, a tetrahydro group, a hexahydrogroup, etc. where hydrogen atoms are added to arbitrary carbon atoms of the aryl. More preferably, it is phenyl or naphthalene.
The xe2x80x9chetero ringxe2x80x9d means a hetero aryl or a saturated hetero ring containing 1 to 4 hetero atoms comprising oxygen, sulfur or nitrogen atoms. Examples of the hetero aryl are a 5- or 6-membered monocyclic hetero aryl (furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazyl, etc.) and a bicyclic hetero aryl where two 5- or 6-membered hetero aryls are fused (naphthylidinyl, benzylfuranyl, indolyl, benzimidazolyl, benzothiadiazolyl, benzoxazinyl, benzothiazolyl, pyridoindolyl, etc.) although not limited those examples. As to the saturated hetero ring, 5- to 7-membered rings are preferred, and piperidyl and piperazinyl are particularly preferred.
With regard to the xe2x80x9csubstituentxe2x80x9d for the xe2x80x9coptionally substituted hydrocarbon ringxe2x80x9d or xe2x80x9coptionally substituted hetero ringxe2x80x9d, any group will do so far as it is a group which is usually able to be substituted to such a ring. Preferred examples are halogen atom (F, Cl, Br, I), lower alkyl, lower alkenyl (vinyl, etc.), lower alkynyl (ethynyl, etc.), xe2x80x94OH, xe2x80x94SH, halogeno lower alkyl (trifluoromethyl, etc.), xe2x80x94O-halogeno lower alkyl, xe2x80x94O-lower alkyl, xe2x80x94S-lower alkyl, xe2x80x94COxe2x80x94O-lower alkyl, xe2x80x94O-lower alkenyl-COxe2x80x94O-lower alkyl, xe2x80x94COOH, xe2x80x94SO2-lower alkyl, xe2x80x94SO-lower alkyl, xe2x80x94CO-lower alkyl, xe2x80x94COxe2x80x94NH2, xe2x80x94COxe2x80x94NH-lower alkyl, xe2x80x94COxe2x80x94N(lower alkyl)2, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NH2, xe2x80x94NH-lower alkyl, xe2x80x94N(lower alkyl)2, xe2x80x94O-lower alkylene-Oxe2x80x94, xe2x80x94NHxe2x80x94CO-lower alkyl and ketone (xe2x95x90O). The substitution may be done with 1 to 5, and preferably, 1 to 3 substituents.
The compound (I) of the present invention has at least one asymmetric carbon atom and, because of that, there are optical isomers such as (R)-compounds, (S)-compounds, etc., racemates, diastereomers and the like. In addition, there is a geometrical isomer or a tautomer depending upon the type of the substituent. The present invention includes all of those separated isomers or a mixture thereof.
The compound (I) of the present invention may form a salt with an acid. Examples of such salt are acid addition salts with a mineral acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid and with an organic acid such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid and glutamic acid. The present invention further includes a hydrate, a solvate with ethanol, etc. and a polymorph of the compound (I) of the present invention.
The compound of the present invention still further includes all of the so-called prodrugs which are metabolized in vivo and converted to a compound having the above-mentioned general formula (I) or a salt thereof. With regard to a group which forms the prodrug of the compound of the present invention, the groups which are described in Prog. Med., 5:2157-2161(1985) and the groups which are described on pages 163-198, Vol. 7 xe2x80x9cMolecular Designxe2x80x9d in xe2x80x9cIyakuhin no Kaihatsuxe2x80x9d, published by Hirokawa Shoten in 1990 may be exemplified.
(Preparation Method)
The compound (I) of the present invention may be prepared by utilizing various preparation methods. As hereunder, representative preparation methods will be illustrated.
First Preparation Method 
(In the formulae, R1, R2, R3, R4, R5, m, n, q and ring D have the meanings as defined already.)
This preparation method is a method where an amino compound (II) is subjected to an amidation reaction using acrylic acid to give a compound (III), which is then subjected to a Michael addition reaction to a cyclic amino compound (IV) to give a compound (I) of the present invention.
In the amidation reaction, it is possible to use acid halides such as acid chloride and acid bromide, acid azides, activated esters with N-hydroxybenzotriazole (HOBT), p-nitrophenol and N-hydroxysuccinimide, etc., dicyclohexylcarbodiimide (DCC), carbodiimidazole (CDI) and other condensing agent. The Michael addition reaction may be carried out, for example, with ice-cooling, at room temperature or under the condition with heating in a solvent such as toluene, benzene, tetrahydrofuran, dichloroethane, alcohols or dioxane. It is also possible to add an additive such as triethylamine, Triton B, potassium hydroxide, etc.
Second Preparation Method 
(In the formulae, R1, R2, R3, R4, R5, A, m, n, q and ring D have the meanings as defined already; X is a leaving group; and Y is a protective group.)
This preparation method is a method where a cyclic amino compound (IV) is subjected to a conventional alkylation reaction using a compound (V), followed by deprotecting the protective group of the carboxylic acid to give a compound (VI), which is then conducted with an amino compound (II) by a conventional amidation reaction, or the cyclic amino compound (IV) is alkylated with a separately synthesized compound (VII).
Third Preparation Method 
(In the formulae, R1, R2, R3, R4, R5, A, m, n, q, ring D and X have the meanings as defined already; and P is a protective group.)
This preparation method is a method where a cyclic amino compound (IV) is subjected to a conventional alkylation reaction using a compound (VIII), the protective group of the amino group is deprotected to give a compound (IX), which is then conducted with a carboxylic acid (X) or a derivative thereof, or a method where the cyclic amino compound (IV) is alkylated with a separately synthesized compound (XI).
Fourth Preparation Method 
(In the formulae, R1, R2, R3, R4, R5, A, P, m, n, q, ring D and X have the meanings as defined already.)
This preparation method is a method where a cyclic amino compound (IV) is subjected to a conventional reductive alkylation reaction using a compound (XII), followed by deprotecting the protective group of the amino group to give a compound (XIII), which is then conducted with a carboxylic acid (X) or a derivative thereof by a conventional amidation reaction, or a method where the cyclic amino compound (IV) is subjected to a conventional reductive alkylation reaction using a separately synthesized compound (XIV). The reductive alkylation reaction is a method where the cyclic amino compound (IV) is reacted with the compound (XII) or the compound (XIV), and the resulting Schiff base is reduced after being isolated or without being isolated. The reduction may be carried out by reaction upon addition of a reducing agent such as a metal hydride complex (sodium borohydride, lithium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, etc.) or borane, or by hydrogenation.
The reaction product prepared by each of the above-mentioned preparation methods is isolated and purified as a liberated compound or a salt, or various solvates such as a hydrate thereof. The salt can be prepared by a usual salt-preparation treatment.
The separation and purification are carried out by applying a usual chemical operation such as extraction, concentration, evaporation, crystallization, filtration, recrystallization and various chromatographic means.
Various isomers can be separated by customary methods utilizing physico-chemical differences among the isomers, and optical isomers can be separated by a usual racemic resolution such as fractional crystallization or chromatography. The optical isomer can also be synthesized from an appropriate optically active starting material.
With regard to the fractional crystallization, fractional crystallization using an optically active organic acid such as tartaric acid derivatives, mandelic acid derivatives and camphorsulfonic acid derivatives may be appropriately carried out. As the solvent, those with which optical resolution is efficiently carried out are appropriately selected.
The compounds of the present invention have an effect of inhibiting the If current and exhibit a strong and specific activity of selectively lowering the cardiac rate and reducing the oxygen consumption of cardiac muscle, whereby they are useful as preventive and therapeutic agents for ischemic cardiac diseases such as angina and cardiac infarction and for circulatory diseases such as congestive cardiac insufficiency and arrhythmia.
The compounds of the present invention are particularly highly useful for prevention and therapy of various clinical symptoms caused by the imbalance between supply and consumption of cardiac muscle oxygen such as pectoral angina, cardiac infarction and arrhythmia accompanied therewith and for prevention and therapy of arrhythmia, particularly supraventricular arrhythmia.
In addition, the compounds of the present invention are expected to have an effect of reducing the complications of atherosclerosis, particularly coronary atherosclerosis, by restricting the vascular hemodynamics compression. Further, the compounds of the present invention suppress an excessively increased cardiac rate and are a drug useful in controlling the cardiac rate to a constant state during the general surgical operation, etc.
Since the compounds of the present invention directly act on the If current in the above-mentioned cardiac rate lowering effect, it has been confirmed that they have no suppressive effect on atrioventricular conduction and systolic function and have a high selectivity to a cardiac rate lowering effect to visual hindrance. With regard to the ion current contributing in the formation of action potential in heart, it has been known that the current which permeates Na channel, K channel and Ca channel is present besides the If current. However, since the compounds of the present invention do not show a significant inhibitory effect to the above-mentioned ion current existing in heart other than the If current at a dose by which the If current is inhibited, it is also expected that the compounds have less side effects caused by inhibition of the current other than the If current. Further, the compounds of the present invention are not accompanied by serious side effects such as convulsion. Accordingly, the compounds of the present invention are useful for prevention and therapy of the above-mentioned various diseases as a cardiac rate lowering agent having less side effects. The compounds of the present invention are furthermore useful as a suppressor for ectopic automatism acceleration or triggered activity caused by the If current in some symptoms such as cardiac infarction and hypertension.
Since the compounds of the present invention lower the cardiac rate by inhibiting the If current, they are also useful as therapeutic agents for cardiac insufficiency and for arrhythmia.
Pharmacological effects of the compounds of the present invention were confirmed according to the following test methods.
(Test Methods)
1. Test on Inhibition of If Current
Test on inhibition of If current was carried out by a method according to Robert, E., et al., Br. J. Pharmacol., 110:343-349, 1993.
 less than Isolation of Cardiac Muscle greater than 
Male guinea pigs of a Hartley strain having a body weight of about 200 to 400 g were fainted away by knocking the head, and then a heart was quickly excised under bleeding by cutting the carotid artery. The heart was transferred to a Tyrode""s solution which was fully aerated with a mixed gas of 95% oxygen and 5% carbon dioxide gas and a sinoatrial node (pacemaker) site (about 3xc3x975 mm) was cut out. The cut-out sinoatrial node was subjected to an enzymatic treatment at 37xc2x0 C. for about 30 minutes in a Ca2+-free Tyrode""s solution containing collagenase (1.5 mg/ml) (manufactured by Yakult Honsha Co., Ltd.). Thereafter, it was allowed to stand at 4xc2x0 C. for 1 hour or more in a K+ rich solution (KB recovery solution). The sinoatrial node site after the treatment was minced with an injection needle and subjected to pipetting to give isolated cardiac muscle cells.
 less than Measurement of Current greater than 
The resulting isolated cardiac muscle was scattered in a chamber for exclusive use, and a patch clamp method (a whole cell mode) was applied to the spindle-shaped cells carrying out a spontaneous contraction. The holding potential was made xe2x88x9240 mV and, a hyperpolarization pulse (for 1 second) was successively applied from this potential to xe2x88x9210, xe2x88x9220, xe2x88x9230, . . . and xe2x88x9280 mV, to induce the If current. The If current at the hyperpolarization pulse of xe2x88x9280 mV was biggest, and therefore, with regard to the evaluation of the pharmacological effect, an effect of the test compound to the If current induced by the pulse of xe2x88x9280 mV was evaluated.
 less than Evaluation of Pharmacological Effect greater than 
An extracellular solution(Tyrode""s solution) containing the test compound was started to be perfused and, with intervals of 5 seconds each, the If current was induced by a hyperpolarization pulse of xe2x88x9280 mV and was recorded until about 100th pulse (for about 8 minutes). An effect of the drug was confirmed to become in a saturated state at 90 pulses or more. With regard to the If current inhibitory effect of the test compound, each of the If currents obtained before the perfusion and after the 90th pulse was measured, and the comparison was made in terms of the concentration (IC50) of the substance inhibiting the If current to an extent of 50%.
The result was that the IC50 value of the compounds of the Examples of the present invention was 10xe2x88x928 M to 10xe2x88x925 M.
2. Test on Cardiac Rate Lowering Effect
The test on cardiac rate lowering effect was carried out by a method according to Walter, K., et al. Eur. J. Pharmacol., 104(1-2):9-18, 1984.
Male guinea pigs of a Hartley strain having a body weight of about 250 to 400 g were fainted away by knocking the head and killed by draining out the blood, and the heart was excised. A right atrium sample was prepared in a Tyrode""s solution which was fully aerated with 95% oxygen and 5% carbon dioxide gas. The sample was applied to a hook made of stainless steel and suspended at a load tension of 1.0 g in a Magnus tube filled with a Tyrode""s solution which was well aerated with 95% oxygen and 5% carbon dioxide gas, whereby the spontaneously pulsing cardiac rate was recorded. After suspending, the sample was allowed to stand for a stabilization period of 1 hour or more, the test compound was cumulatively added into a Magnus tube every 30 to 45 minutes and a concentration vs. effect curve was determined from the data after 30 minutes from the administration of the substance, whereby the effect was judged. The cardiac rate lowering effect was compared in terms of the concentration (EC30) of the substance which lowered the spontaneous cardiac rate to an extent of 30% from the data before the administration. The result was that the compounds of the present invention showed a strong cardiac rate lowering effect. The result of the tests is shown in Table A.
3. Test on Convulsion Expression
Male rats of a Wister strain having a body weight of 250 to 350 g under awaking were fixed in a cage, and the test compound was administered from a tail vein. The test compound was administered at a dose of either 20 mg/kg (i.v.) or 40 mg/kg (i.v.) once for each rat. After administration of the test compound, behavior of the animal was observed for about 1 hour without restraint. The influence of the test compound on the spontaneous behavior of the rat was evaluated by the fact whether or not the convulsion was noted within the observed period.
The result was that there were compounds showing no convulsion-inducing effect even by an intravenous administration of 40 mg/kg while the compound of Example 8 of Japanese Patent Laid-Open No. 138172/1990 and the compounds of Examples 24 and 33 of WO 98/13364 cited in the Background of the Invention showed a convulsion-inducing effect at a dose of 20 mg/kg which was one half of the above (Table B).
From the above result, it is now apparent that, when an amide moiety which is a structural characteristic of the compounds of the present invention is introduced, the compounds of the present invention do not show an convulsion-inducing effect but effectively inhibit the If current showing a cardiac rate lowering effect.
A pharmaceutical composition containing one, two or more of the compounds of the present invention or salts thereof are prepared using a usual pharmaceutically acceptable carrier.
Administration of the pharmaceutical composition in the present invention may be any route of oral administration and parenteral administration such as by means of injection agents, suppositories, percutaneous agents, inhalation agents or vesicoclysis.
The dose may be appropriately decided for each case taking into consideration symptom, age and sex of the subject, etc. and, in the case of oral administration, it is usually about 0.1 mg/kg to 100 mg/kg per day for an adult. The administration is effected at once or by dividing into 2 to 4 times a day. In the case of an intravenous injection which is carried out depending upon the symptom, it is usually about 0.01 mg/kg to 10 mg/kg per day for an adult. The administration is effected at once or by dividing into one to several times a day.
With regard to a carrier for the pharmaceutical preparation, solid or liquid nontoxic substances for drugs may be exemplified.
With regard to a solid composition for oral administration according to the present invention, there are used tablets, pills, capsules, diluted powder, granules, etc. In such solid compositions, one or more active ingredients are mixed with at least one inert diluent such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, agar, pectin or magnesium metasilicate aluminate. The composition may contain additives other than the inert diluent, for example, lubricants such as magnesium stearate, disintegrating agents such as calcium cellulose glycolate, stabilizers such as lactose and solubilization aids such as glutamic acid or aspartic acid according to a conventional method. If necessary, tablets or pills may be coated with sugar coats such as sucrose, gelatin, hydroxypropyl cellulose or hydroxypropylmethyl cellulose phthalate or with films which are soluble in stomach or in intestine.
The liquid composition for oral administration includes a pharmaceutically acceptable emulsion, solution, suspension, syrup, elixir or the like, or a commonly used inert diluent such as purified water or ethanol. Besides the inert diluent, the composition may further contain auxiliary agents such as moisturizers and suspending agents, sweeteners, flavors, fragrances or antiseptics.
The injection solution for a parenteral administration includes aseptic aqueous or non-aqueous solutions, suspensions and emulsions. The aqueous solutions and suspensions contain, for example, distilled water for injection and physiological saline. Examples of the non-aqueous solutions and suspensions are ethylene glycol, propylene glycol, polyethylene glycol, vegetable oils such as cacao butter, olive oil and sesame oil, alcohols such as ethanol, gum arabic and Polysolvate 80 (trade name). Such composition may further contain additives such as isotonizing agents, antiseptics, moisturizers, emulsifiers, dispersing agents, stabilizers (such as lactose), and solubilization aids (such as glutamic acid or aspartic acid). They may be asepticized, for example, by filtration through a bacteria-keeping filter, by compounding with a bactericide, or by irradiation. They may also be used in such a manner that an aseptic solid composition is prepared, and then, before use, the composition is dissolved in an aseptic water or in an aseptic solvent for injection.
Hereunder, the desired compounds of the present invention and the preparation methods thereof will be further illustrated by way of the Examples although the present invention is never limited by those Examples. Incidentally, methods for the preparation of the starting compounds for the compounds of the present invention will be mentioned in the Referential Examples.
A conventional acylation reaction was carried out using a tetrahydrofuran solution (30 ml) of 4.6 g of 3,4-dimethoxyaniline, 5.0 ml of triethylamine and 2.68 ml of acryloyl chloride to give 5.22 g of 3,4-dimethoxyacrylanilide as white crystals.
The compounds of Referential Examples 1-1 to 1-9 were synthesized by the same manner as in Referential Example 1 (see Table 1 shown later).
A conventional amidation reaction was carried out using a dichloromethane solution (40 ml) of 2.53 g of (xc2x1)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, 3.0 g of N-(tert-butyloxycarbonyl)nipecotic acid, 3.0 g of 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride and 0.89 g of 1-hydroxybenztriazole to give 3.77 g of (xc2x1)-6,7-dimethoxy-2-{[1-(tert-butyloxycarbonyl)-3-piperidyl]carbonyl}-1,2,3,4-tetrahydroisoquinoline. Deprotection of 3.77 g of (xc2x1)-6,7-dimethoxy-2-{[1-(tert-butyloxycarbonyl)-3-piperidyl]carbonyl}-1,2,3,4-tetrahydroisoquinoline was further carried out using 10 ml of an ethyl acetate solution containing 4N hydrochloric acid to give 2.30 g of (xc2x1)-6,7-dimethoxy-2-[(3-piperidyl)carbonyl]-1,2,3,4-tetrahydroisoquinoline hydrochloride as colorless crystals.
The compounds of Referential Examples 2-1 to 2-11 were synthesized by the same manner as in Referential Example 2 (see Table 1 shown later).
(xc2x1)-6,7-Dimethoxy-2-[(3-piperidyl)carbonyl]-1,2,3,4-tetrahydroisoqinoline hydrochloride (3.19 g) was desalted by a customary method, and a conventional alkylation reaction was carried out using an acetonitrile solution (30 ml) of the residue, 2.85 g of N-(2-bromoethyl)phthalimide and 1.55 g of potassium carbonate to give 3.83 g of (xc2x1)-6,7-dimethoxy-2-{[3-(2-phthalimidoethyl)piperidyl]carbonyl}-1,2,3,4-tetrahydroisoquinoline. Then, 3.83 g of (xc2x1)-6,7-dimethoxy-2-{[3-(2-phthalimidoethyl)piperidyl]carbonyl}-1,2,3,4-tetrahydroisoquinoline was deprotected by a customary method using 45 ml of a methanolic solution containing 40% of methylamine to give 2.67 g of (xc2x1)-2-{[3-(2-aminoethyl)piperidyl]carbonyl}-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline as a yellow foamy substance.
The compounds of Referential Examples 3-1 to 3-4 were synthesized by the same manner as in Referential Example 3 (see Table 1 shown later).
A conventional alkylation reaction was carried out using a dimethylformamide solution (10 ml) of 1.77 g of 2-(3,4-dimethoxyphenyl)acetonitrile, 1.00 g of sodium hydride and 4.26 g of methyl iodide to give 1.78 g of 2-(3,4-dimethoxyphenyl)-2-methylpropionitrile. A conventional catalytic hydrogenation reaction was carried out using an ethanolic solution (30 ml) of 1.75 g of 2-(3,4-dimethoxyphenyl)-2-methylpropionitrile, 3.0 ml of an aqueous 28% ammonia solution and 4.3 g of Raney nickel to give 1.59 g of 2-(3,4-dimethoxyphenyl)-2-methylpropylamine. Then, a conventional cyclization reaction was carried out using a formic acid solution (8 ml) of 1.58 g of 2-(3,4-dimethoxyphenyl)-2-methylpropylamine and 0.252 g of paraformaldehyde to give 1.34 g of 6,7-dimethoxy-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline as a pale yellow oily substance. A conventional alkylation reaction was carried out using a solution (10 ml) of 1.77 g of 2-(3,4-dimethoxyphenyl)acetonitrile in dimethylformamide, 1.00 g of sodium hydride and 4.26 g of methyl iodide to give 1.78 g of 2-(3,4-dimethoxyphenyl)-2-methylpropionitrile.